# Dynamic regulation of axonal trafficking and surface distribution of Nav1.7 in sensory neurons

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2022 · —

## Abstract

Chronic pain is common among Veterans and remains an unmet medical need. Voltage-gated sodium
channels (NaVs) that are expressed preferentially in primary afferents play a critical role in human pain
disorders, and present opportune targets for the development of novel pain treatments that carry minimal CNS
side effects and addictive potential. NaV1.7 is a peripheral threshold channel that regulates action potential
firing and neurotransmitter release. Our work for the past 15 years has linked NaV1.7 to human pain disorders,
e.g., inherited erythromelalgia, small fiber neuropathy, painful diabetic neuropathy, and validated NaV 1.7 as a
highly attractive target for the treatment of pain. Although considerable progress has been made in the
development of novel NaV1.7 blockers for the treatment of pain, much work is needed to improve their
specificity and efficacy. Similarly, while existing NaV blockers can provide symptomatic relief in patients, their
utility is limited due to non-specificity and significant CNS side effects.
Gabapentinoids, the current first line treatment for chronic pain, inhibit trafficking of presynaptic voltage-gated
calcium channel to the plasma membrane or disrupt Rab11-dependent recycling, thus reducing calcium
currents and transmitter release. By analogy to gabapentinoids' mode of action for the treatment of pain, and
recent focus on trafficking proteins as therapeutic targets in CNS disorder, targeting trafficking machinery of
Nav1.7 might represent a novel approach to pain treatment. However, little is known about molecules and
mechanisms that control sodium channel trafficking and surface distribution along the length of sensory
axons—a target of opportunity that we explore in this proposal.
In this proposal, we aim to elucidate molecular mechanisms that control trafficking of NaV1.7 and their
distribution in the axonal plasma membrane of sensory neurons, in an effort to identify potential new targets for
the treatment of chronic pain. Specifically, we will build upon a powerful new platform that we developed, that
enables real-time imaging of single sodium channels within living sensory neurons at a distance from the soma
with unprecedented spatial- and temporal-resolution.
Knowledge gleaned from these studies will provide unprecedented clarity about mechanisms that regulate sub-
cellular distribution of sodium channels in sensory neurons, particularly along the length of axons, in normal
and disease states. These studies, in turn, will enable discovery of new targets for treatment of chronic pain.
Our ultimate goal is to develop safer and more effective treatments without addictive potential and other
serious side effects.

## Key facts

- **NIH application ID:** 10293536
- **Project number:** 5I01BX004899-02
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** Sulayman D Dib-Hajj
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293536

## Citation

> US National Institutes of Health, RePORTER application 10293536, Dynamic regulation of axonal trafficking and surface distribution of Nav1.7 in sensory neurons (5I01BX004899-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10293536. Licensed CC0.

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